CYP2D6 in patients with Porphyria.

LAVANDERA JIMENA; BUZALEH ANA MARIA; PARERA VICTORIA; BATLLE ALCIRA

Kingston-Upon-Hull, UK

Congreso; TETRAPYRROLE DISCUSION GROUP MEETING; 2005

TETRAPYRROLE DISCUSION GROUP

The polymorphisms of the enzyme CYP2D6 result in poor (PM), intermediate (IM), ultrarrapid (UM) and extensive metabolizers (EM). When EM are heterozygous they are classified as extensive intermediate metabolizers (EIM). Porphyrias are inherited disorders of heme metabolism and a number of  drugs are involved in the triggering of these diseases. The polymorphisms of CYP2D6 affect the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. Some of these drugs are unsafe for their use in porphyric patients. So, the aim of this work was to investigate if there is some association between the different types of porphyrias and the PM phenotype  of CYP2D6. The frequency of CYP2D6A and CYP2D6B alleles associated with PM phenotype was studied in a population of individuals with Porphyria Cutanea Tarda (PCT) (n=15), Acute Intermittent Porphyria (AIP) (n=20) and Variegate  Porphyria (PV) (n=20); in comparison with healthy controls (C) (n=51). A group of individuals with Fe elevated  (Fe) (n=19) was also evaluated. Alleles were detected by  PCR-RFLP. Results indicated that 39% of C group showed EIM phenotype (20/51); 17 of then carrying  the CYP2D6B allele and 3 of then carrying the CYP2D6A allele. 3.9% C group were PM (2/51), one of these subjects carried  CYP2D6B allele and the others one CYP2D6A allele. Among the porphyric population studied, 10% PAI (2/18),  26.6% PCT (4/15) and 26.6% PV (4/15) showed EIM phenotype. In PAI and PCT subjects, only the CYP2D6B allele was found; while one individual of PV group carried the CYP2D6A allele. 6.6%  PCT and PV were PM; the allele CYP2D6B was found in  PCT group while PV group carried both alleles.   Among Fe group,  15.7% were  PM (3/19) and 15.7% EIM (3/19) carrying only the CYP2D6B allele. When we analyze the results obtained in all the porphyric patients studied, the frequency of EIM phenotype was lower (pz0.05) than in healthy controls. A similar pattern was detected for EIM phenotype in PAI group in comparison with C group.  Results here presented, yet preliminary, demonstrate, for the first time, that 24% of porphyric subjects carried  the CYP2D6B allele and only 2% carried the CYP2D6A allele. The polymorphisms of the enzyme CYP2D6 result in poor (PM), intermediate (IM), ultrarrapid (UM) and extensive metabolizers (EM). When EM are heterozygous they are classified as extensive intermediate metabolizers (EIM). Porphyrias are inherited disorders of heme metabolism and a number of  drugs are involved in the triggering of these diseases. The polymorphisms of CYP2D6 affect the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. Some of these drugs are unsafe for their use in porphyric patients. So, the aim of this work was to investigate if there is some association between the different types of porphyrias and the PM phenotype  of CYP2D6. The frequency of CYP2D6A and CYP2D6B alleles associated with PM phenotype was studied in a population of individuals with Porphyria Cutanea Tarda (PCT) (n=15), Acute Intermittent Porphyria (AIP) (n=20) and Variegate  Porphyria (PV) (n=20); in comparison with healthy controls (C) (n=51). A group of individuals with Fe elevated  (Fe) (n=19) was also evaluated. Alleles were detected by  PCR-RFLP. Results indicated that 39% of C group showed EIM phenotype (20/51); 17 of then carrying  the CYP2D6B allele and 3 of then carrying the CYP2D6A allele. 3.9% C group were PM (2/51), one of these subjects carried  CYP2D6B allele and the others one CYP2D6A allele. Among the porphyric population studied, 10% PAI (2/18),  26.6% PCT (4/15) and 26.6% PV (4/15) showed EIM phenotype. In PAI and PCT subjects, only the CYP2D6B allele was found; while one individual of PV group carried the CYP2D6A allele. 6.6%  PCT and PV were PM; the allele CYP2D6B was found in  PCT group while PV group carried both alleles.   Among Fe group,  15.7% were  PM (3/19) and 15.7% EIM (3/19) carrying only the CYP2D6B allele. When we analyze the results obtained in all the porphyric patients studied, the frequency of EIM phenotype was lower (pz0.05) than in healthy controls. A similar pattern was detected for EIM phenotype in PAI group in comparison with C group.  Results here presented, yet preliminary, demonstrate, for the first time, that 24% of porphyric subjects carried  the CYP2D6B allele and only 2% carried the CYP2D6A allele.